SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”